Many drugs are not suitable for passive drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body, as for example, through intact skin. This concept is based upon basic principles of electrochemistry. An electrochemical cell in its simplest form consists of two electrodes and associated half cell reactions, between which electrical current can flow. Electrical current flowing through the metal portion of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid phase is carried by ions (ionic conduction). Current flows as electrical charge is transferred to chemical species in solution by means of oxidation and reduction charge transfer reactions at the electrode surfaces. A detailed description of the electrochemical processes involved in electrically-assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard & L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980). Therefore, only pertinent portions will be presented here.
Electrically-assisted transport or electrotransport, is defined as the mass transport of a particular chemical species in the presence of an electric potential. Typically, said transport is through a biological interface or membrane when the electrical potential gradient is imposed across it. Three physical processes contribute to transport under these conditions: passive diffusion, electromigration and convection.
The Nernst-Planck equation (1) expresses the sum of these fluxes for any particular chemical species i in the presence of an electrical field, .gradient..PHI.. EQU J.sub.i =-[D.sub.i .gradient.C.sub.i ]-[z.sub.i F u.sub.i C.sub.i .gradient..PHI.]+[C.sub.i v] (1)
where
J.sub.i =flux of species i (moles/cm.sup.2 -sec) PA1 D.sub.i =diffusion coefficient of i (cm.sup.2 /sec) PA1 .gradient.=the gradient operator PA1 C.sub.i =concentration of i PA1 z.sub.i =number of charges per molecule of i PA1 F=Faraday's constant (96,500 coulombs/mole of charge) PA1 u.sub.i =mobility of i (velocity/force=sec/g) PA1 .PHI.=electrical potential (volts) PA1 v=velocity vector (cm/sec) PA1 J.sub.i,x =the total electrically-assisted flux of species i in the x direction PA1 E.sub.x =-(d.PHI./dx)=the electrical field in the x direction i.e. the negative of the electrical potential gradient PA1 v.sub.x =the x component of the velocity vector PA1 I=the total current passing through the medium PA1 A=the area through which the current passes PA1 .epsilon.=the dielectric constant of the liquid medium PA1 .zeta.=the zeta potential of the membrane having a fixed charge PA1 .kappa..degree.=the conductivity of the liquid phase PA1 .mu.=the viscosity of the liquid phase
The Nernst-Plank equation (1) has three terms, one for each of the physical processes contributing to the mass transport. The first term is the flux due to passive diffusion and is proportional to the concentration gradient of species i. The second term is the flux due to electromigration, where the driving force is the gradient of electrical potential, i.e., the electric field strength. The third term is the flux due to convection or electroosmosis, where the mechanism of transport is the movement of material by bulk fluid flow which is determined by the magnitude and direction of the bulk fluid velocity vector.
Considering transport in only one direction of a rectilinear coordinate system, equation (1) may be simplified to: EQU J.sub.i,x =-[(D.sub.i) (dC.sub.i /dx)]+[z.sub.i F u.sub.i C.sub.i E.sub.x ]+[C.sub.i v.sub.x ] (2)
where
Equation (2) applies within each and every phase, and the physical constants and extensive properties must be applicable to the phase of interest. For the case of an electrotransport transdermal system positioned on the skin, one form of equation (2) holds within the drug containing reservoir of the electrotransport system where D.sub.i, c.sub.i, u.sub.i, etc., are the diffusion coefficient, concentration and mobility of species i within the system. Another identical form of equation (2) holds within the skin (assuming the skin is uniform) except that the diffusion coefficient, concentration and mobility of species i are now those within the skin. The extensive properties of these equations such as the concentration and electric field strength are linked at the interface by an appropriate proportionality constant such as the partition coefficient and the ratio of dielectric constants, respectively.
The second term in equation (2) describes the flux due to electromigration. Typically written in terms of the electrical field, it is often more convenient to express electromigration in terms of the electrical current. By using the transference number of species i, t.sub.i, which is the fraction of current carried by species i, the electromigration flux of species i, J.sub.i,EM, may be expressed as the product of the transference number and the current density passing through the medium: EQU J.sub.i,EM [(t.sub.i) (I)]/A (3)
where
The third term in equation (2) describes the flux due to convection. Disregarding the possibility of significant hydrostatic pressure gradients across the membrane or chemical osmosis driving forces, and assuming the membrane has a fixed surface charge, it can be said that the only means of moving an appreciable amount of fluid across a membrane is through electroosmosis. Electroosmosis is defined as bulk fluid flow entrained by the migration of unpaired excess ions moving in response to an applied electric field. The electroosmotic flux of species i, J.sub.i,EO, is related to the total current passing through the membrane by the following equation: EQU J.sub.i,EO =(.epsilon..zeta.I)/(.kappa..degree..mu.A) (4)
where
Equations (3) and (4) demonstrate that the second and third terms of equation (2) may be written as functions of the total current passed through a system. Hereinafter, the sum of these two terms will be referred to as the electrokinetic flux, J.sub.EK.
As stated earlier, the first term of equation (2) is the passive diffusion term. This term is identical to that when passive diffusion is the only mechanism of mass transfer, i.e., it is independent of the electrical conditions of the system. This term will hereinafter by referred to as the passive flux component, J.sub.P. The sum of all three terms in equation (2) will be called the electrically-assisted flux, J.sub.EA : EQU J.sub.EA =J.sub.P +J.sub.EM +J.sub.EO ( 5)
Since the electrokinetic flux, J.sub.EK, is the sum of the flux due to electromigration and the flux due to electroosmosis, equation (5) can be simplified to: EQU J.sub.EA =J.sub.P +J.sub.EK ( 6)
A membrane which mimics the behavior of skin must exhibit the following mass transport properties: transport by convection should be negligible at high ionic strength, resistance to passive diffusion should be high, and resistance to electromigration should be relatively low. Ideally, when no electric field is imposed on the membrane, i.e., no current is passed across the membrane, no drug flux should be detected. When a field is applied and current is caused to flow across the membrane, appreciable drug flux should be detected. Furthermore, a relatively small voltage should be required in that a 100 .mu.A/cm.sup.2 current would require less than 1 volt.
The concept of electrotransport in drug delivery is known, and there are a number of categories in which drug delivery systems utilizing electrotransport principles can offer major therapeutic advantages. See P. Tyle & B. Kari, "Iontophoretic Devices" in DRUG DELIVERY DEVICES, pp. 421-454 (1988). There is a continuing need to develop systems with improved characteristics, specifically improved control of the drug delivery. State of the art rate controlling membranes such as are taught in U.S. Pat. No. 3,797,494, are suitable for passive transport but do not provide control over electrically-assisted delivery. Therefore, there is a need for a membrane which may be used to limit or control the electrically-assisted release from the system. Further, there is a need for an electrotransport drug delivery system which has a control membrane to inhibit the release of drug from the system when no current is flowing. The main feature is that use of such a membrane, by eliminating or greatly reducing passive transport, would allow release of the drug to be turned on and off, by simply turning the electric field (current) on and off.
Such a membrane would also provide a safety feature to prevent excess drug delivery from occurring if the electrotransport system is placed on abraded skin or on a body surface which has somehow been compromised. Further, such a safety feature would inhibit drug release during handling of the system.
Along with the growing interest in the development of electrotransport systems, there is a growing need for improved techniques of testing the properties of said systems. For example, state of the art techniques for measuring the in vitro release rates of passive transdermal systems are inadequate for testing electrotransport systems. Typically, such testing utilizes a synthetic membrane such as Hytrel.RTM. or an ethylene vinyl acetate copolymer such as EVA 9, which exhibit characteristics similar to that of skin during passive drug diffusion. There is a need for a synthetic membrane that exhibits electrically-assisted ionic transport properties similar to that of skin.
Another use for such a membrane would be for system stability testing. Human cadaver skin cannot be used for this application because of the extent of natural donor to donor variation and large supplies are often needed for quality control, which are not always readily available. For stability testing, a membrane must behave consistently over time in order to provide an accurate measure of system stability.